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Mini Review
Cancer Reports and Reviews
Cancer Rep Rev, 2020 doi: 10.15761/CRR.1000202 Volume 4: 1-4
ISSN: 2513-9290
Do we need cost-effectiveness analysis of brachytherapy for 
cervical cancer in the 3D image-guided era?
Suzumura EA1*, Gama LM2, de Carvalho HA2 and de Soárez PC1
1Departamento de Medicina Preventiva, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
2Departamento de Radiologia e Oncologia, Divisao de Radioterapia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
Abstract
Cervical cancer is the second most prevalent cancer in the female population. Intracavitary brachytherapy is considered an essential component of the disease 
management. In conventional brachytherapy, treatment planning is performed using X-ray imaging to visualize the pelvic bones structures and applicators, considering 
point A as the reference for dose delivery. For the last years, three-dimensional (3D) image-guided brachytherapy, with the use of computed tomography or magnetic 
resonance imaging, has been used to determine tumor volume and shape, as well as the healthy organs at risk, and prescribed dose is delivered to an ‘at-risk’ volume. 
Although 3D brachytherapy shows technical advantage and potentially superior clinical outcomes over conventional, 3D planning does carry added costs. The decision 
about incorporating new health technologies in health care systems should be based in multiple aspects, including financial issues. Economic evaluation studies have 
been adopted as a method for supporting efficient resource allocation. Cost-effectiveness analysis, in particular assessing consequences as quality-adjusted life years 
(QALYs) or disability-adjusted life years (DALYs), that is cost-utility analysis, are the preferred type of economic evaluation study for decision-making on technology 
incorporation. Evidence from economic evaluation studies are not transferrable to other health care systems with distinct health policies, resources and priorities, 
therefore, whether the benefits afforded by 3D brachytherapy are cost-effective is to be determined withing each health care system considering local context.
*Correspondence to: Erica Aranha Suzumura, Departamento de Medicina 
Preventiva, Faculdade de Medicina FMUSP, Universidade de Sao Paulo. Av Dr 
Arnaldo 455, CEP: 01246903, Sao Paulo, SP, Brazil, E-mail: esuzumura@yahoo.com.br
Key words: brachytherapy, uterine cervical neoplasms, economic evaluations, cost-
effectiveness analysis
Received: March 13, 2020; Accepted: March 25, 2020 Published: March 30, 
2020
Introduction
Cervical cancer is the second most prevalent cancer in the female 
population [1]. In 2018, the World Health Organization (WHO) 
estimated that 570,000 new cases were diagnosed, and approximately 
311,000 women died of cervical cancer in the world, with 85% of them 
in middle- and low-income countries [1].
The American Cancer Society estimates that in 2020 about 
13,800 new cases of invasive cervical cancer will be diagnosed and 
more than 4,200 women will die from cervical cancer in the United 
States [2]. Cervical cancer was once one of the most common causes 
of death in American women but, as a result of the increase in 
human papillomavirus (HPV) screening, death rates have dropped. 
Nonetheless, cervical cancer mortality rates have not changed much 
over the last 10 years [2].
In Brazil, the National Cancer Institute (INCA) estimates that 
16,590 new cases will be diagnosed in 2020, with an estimated risk of 
15.43 cases per 100,000 women [3]. In 2017, more than 6,300 women 
died from cervical cancer in Brazil [3].
Treatment of cervical cancer
Radiotherapy is an excellent cervical cancer treatment modality 
because of the tolerance of the cervix to high radiation doses [4]. The 
conventional radiotherapy regimen involving conformal external beam 
radiotherapy of the pelvis followed by intracavitary brachytherapy, and 
concomitant chemoradiation, has been the standard of care for locally 
advanced tumors since the early 90’s [4].
Derived from ancient Greek words for ‘short distance’ (brachios) 
and ‘treatment’ (therapy), brachytherapy refers to therapeutic use of 
encapsulated radionuclides within or close to a tumor. It is sometimes 
called Curietherapy, named after its French inventor Pierre Curie [5]. 
Since 1900 brachytherapy has been used in the treatment of cancer and 
is considered an essential component of the disease management [6].
Unlike external beam conformal radiotherapy, in which the tumor 
receives radiation from a source located outside the body, brachytherapy 
involves a more precise placement of radiation sources close to tumor 
site. The greater effectiveness of brachytherapy compared to external 
radiotherapy is attributed to the ability to provide high concentrated 
and more accurate doses to the target tissue, promoting greater local 
control and increasing the safety of adjacent healthy tissues [7]. In 
contrast, brachytherapy is invasive, and requires the insertion of specific 
applicators usually under sedation or anesthesia [5].
In conventional gynecological brachytherapy, treatment planning 
is performed using two-dimensional (2D) X-ray imaging to visualize 
the pelvic bones structures and applicators, using anatomic references 
for planning, without conforming to the tumor shape and size [4]. 
Treatment planning relies on dose points, considering point A as 
the reference for dose delivery. Tumor volume coverage is the most 
important goal for local control. The accurate determination of the 
gross tumor volume (GTV), the clinical target volume (CTV) involving 
the tumor volume and safety margins, as well as the healthy organs 
mailto:esuzumura@yahoo.com.br
Suzumura EA (2020) Do we need cost-effectiveness analysis of brachytherapy for cervical cancer in the 3D image-guided era?
 Volume 4: 2-4Cancer Rep Rev, 2020 doi: 10.15761/CRR.1000202
Retrospective observational studies comparing 3D and 2D 
brachytherapy showed increased local control [17-19], reduced toxicity 
rates [17,18,20], which resulted in improved overall survival [17,21] 
in patients treated with 3D approach. A French multicentric non-
randomized prospective study assessing the clinical effects of the two 
planning strategies showed that 3D brachytherapy also improved local 
control with half the toxicity observed with 2D dosimetry [22-24].
Cervical cancer and its treatment had a negative influence on the 
quality of life of these women. Some studies showed negative effects 
associated to brachytherapy on the domains related to symptoms and 
functionality, which impacts overall quality of life [25]. In this sense, 
as 3D brachytherapy is associated with lower toxicity and late adverse 
effects rates [17,18,20,22-24], it has the potential to reduce symptoms 
and the time to functional recovery, and to improve sexual function 
after the treatment, enhancing patients quality of life.
3D brachytherapy is still evolving, and until now, the results are 
promising. Improving in local control, survival rates and quality of life, 
are really expected by radiation oncologists in the near future.
Understanding economic evaluation studies
The assessment of the effectiveness and safety of an intervention 
are some of the components of the decision-making process regarding 
policies for incorporating new health technologies in health care 
systems. Financial resources are finite and the use of resources in a new 
technology usually determines reallocation from another area [26]. In 
this sense, not only the expected health benefits, but also the costs are 
important issues in the decision. 
Economic evaluation studies have been adopted as a method for 
supporting efficient resource allocation. Data on the effectiveness of an 
intervention are more easily “transferable” from one geographic region 
to another, however, the generalization of results of health economic 
studies is limited, requiring theproduction of reliable information 
contextualized for each country population [26].
For a better understanding, two types of economic evaluation 
studies can be identified in the literature: full and partial studies. Full 
economic evaluation are defined as studies in which (1) two or more 
alternative interventions are compared, and (2) both costs and effects 
(consequences or benefits or outcomes) of the compared treatments are 
taken into account [27]. Full economic evaluation studies are regarded 
as the optimal type of economic evaluation because they are specifically 
designed to inform policy decisions on technology incorporation in 
a health care system. In a partial economic evaluation study, the two 
noted requirements (comparison two treatments and measurement of 
both costs and effects) are not met, and they usually report only costs 
as outcomes [27].
Four types of full economic evaluation studies can be distinguished: 
cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis, 
and cost-minimization analysis. In a cost-effectiveness analysis, costs 
are expressed in monetary values (e.g. Euros, Dollars, Reais, etc.) and 
effects in natural units, such as reduction in toxicities, increase in local 
control or in survival rates [27]. Cost-utility analysis is a special type of 
cost-effectiveness analysis, where the costs are also valued in monetary 
values and effects are typically measured as quality-adjusted life years 
(QALYs) or disability-adjusted life years (DALYs) [27]. 
In cost-benefit analysis, the benefits of health care are expressed to 
an equivalent amount of consumption, that is, the amount of money 
that an individual is willing to pay or to receive in return for the benefits 
at risk (OAR) surrounding the tumor are crucial for better clinical 
outcomes [4]. In addition, the dose offered decreases rapidly as the 
distance from the applicator increases, emphasizing the importance of 
proper placement of the applicators guided by some imaging exam [6]. 
Grade 3-4 hematological toxicity, enteritis and cystitis are 
often the most limiting adverse events associated to conventional 
chemoradiotherapy for cervical cancer and can compromise the 
effectiveness of treatment due to unscheduled interruptions, which 
allows tumor regrowth and influence directly on patients quality 
of life [4]. Therefore, whenever possible it is important to choose a 
radiotherapy technique that protects OAR from excessive toxicity 
in order to reduce the acute side effects and late complications of 
radiotherapy and potentially improve local control through improved 
target coverage [4].
3D image-guided brachytherapy
For the last years, three-dimensional (3D) image-guided 
brachytherapy, with the use of computed tomography (CT) or magnetic 
resonance imaging (MRI), has been used in clinical practice [8]. This 
was a move away from prescribing dose to point A to an ‘at-risk’ volume 
(predominantly, the high-risk CTV [HR-CTV]) [9]. The evaluation 
of dose to OAR has also shifted away from the ICRU 38 reference 
points to a dose volume histogram (DVH) based approach, allowing 
brachytherapy plans to more accurately define where dose will be, 
rather than predicting where it may be [10]. The main advantage of 
3D brachytherapy is the quality of the 3D image and the opportunity 
for dose optimization to more accurately conform to the CTV. In small 
tumors, the irradiated volume can be reduced to decrease the dose to 
OAR, and in larger tumors, the isodose prescription can be expanded 
for better coverage [6,9].
Clinical effects of 3D compared to 2D brachytherapy
Few systematic reviews were published in this field. None of them 
attempted to assess clinical outcomes associated with 3D compared to 
2D brachytherapy in patients with cervical cancer. They aimed to report 
the clinical effects of only one of the image-planning strategies [11-13], 
or to compare the technical usefulness and dosimetry of 3D and 2D 
imaging technologies for brachytherapy planning, without reporting 
clinical outcomes [14].
Randomized trials are the gold standard to assess the effects of 
treatments, however such trials were not published so far. Indeed, these 
would provide the best evidence to compare both techniques. However, 
as in many other radiation treatments, 2D techniques may be associated 
with a higher level of imprecision on dose delivery and toxicity. This is 
not different regarding brachytherapy, that is supposed to deliver very 
high doses to the target. A comprehensive evaluation of tumor volume 
(GTV, CTV and HR-CTV) and OAR is provided by 3D brachytherapy, 
which is being increasingly used worldwide. This can be considered as 
a reflection of the same phenomenon that occurred with external beam 
conformal radiotherapy, resulting in a gradual transition from 2D to 
3D technique.
For instance, the emerging evidence from the large multicentre 
international EMBRACE studies points to a relationship of higher dose 
delivery and more advanced techniques with better outcomes [15,16]. 
In the RetroEMBRACE study, improved local control was associated 
with an overall survival benefit of about 10% compared with historical 
cohorts, with limited severe toxicity [15].
Suzumura EA (2020) Do we need cost-effectiveness analysis of brachytherapy for cervical cancer in the 3D image-guided era?
 Volume 4: 3-4Cancer Rep Rev, 2020 doi: 10.15761/CRR.1000202
offered. In this type of economic evaluation, both costs and effects are 
expressed in monetary terms of the alternative interventions [27].
For cost-minimization analysis the effectiveness of the compared 
interventions is equivalent, thus the main element of the analysis is the 
determination of which of the alternatives will entail lower costs [26]. 
Although cost-minimization analysis is distinguished as a full economic 
evaluation study [26], it is considered as only a costing exercise and not 
a formal economic evaluation for some decision makers, therefore, it is 
not an appropriate reference case analysis [28].
Economic evaluation studies can be based on a modelling study, 
in which various secondary sources of data (e.g. literature, population 
databases) might be used to build a model simulating the course of the 
disease and costs associated, assuming that patients were submitted 
to each of the alternative treatments. Also, economic evaluation 
studies can be trial-based, in which the data for economic analyses are 
collected alongside data from a clinical trial [27]. A third approach is 
also possible using a combination of the previous analytical approaches.
Cost-effectiveness analysis, in particular assessing consequences as 
QALYs or DALYs, that is cost-utility analysis, are the preferred type 
of economic evaluation study for both decision-making on technology 
incorporation in a health care system and clinical practice guidelines 
development.
The result of cost-effectiveness analysis can be expressed in a 
summary measure called incremental cost-effectiveness ratio (ICER), 
with is defined as the difference in expected costs between two 
alternative interventions divided by the difference in expected effects 
[27,28]. It represents the average incremental cost associated with one 
additional unit of the measure of consequences (e.g., cases avoided, 
increase in survival, QALYs or DALYs). The ICER can be estimated as 
presented below, where Ci and Ei are the cost and effect in patients who 
received (or would receive) the intervention; and Ca and Ea are the cost 
and effect in patients who received (or would receive) the alternative 
usual treatment:
ICER=(Ci-Ca)/(Ei-Ea)
An intervention with a lower ICER (e.g., spending US$ 1000 on 
an intervention that would increase QALYs by 1 year) would indicate 
a good value for money intervention, while a higher ICER (e.g., 
spending US$ 1,000,000 to increase QALYs by 1 year) would typically 
be considered a low value for money intervention [29]. Nevertheless, 
objectively,what defines if an intervention is cost-effective is known as 
“willingness-to-pay threshold”. 
A willingness-to-pay threshold represents an estimate of what a 
consumer of health care might be prepared to pay for the health benefit 
given other competing demands on that consumer’s resources [30]. 
Therefore, to set a willingness-to-pay threshold many relevant factors, 
such as the opportunity cost and affordability within the context of the 
health care system, have to be taken in account. 
The use of any single willingness-to-pay threshold is ultimately 
arbitrary and is widely criticized in health policy circles [29]. 
Researchers have attempted in various ways to deduce what constitutes 
a reasonable threshold on the basis of economic theory or empirical 
estimates [31], however an international debate is currently under way 
on the need for countries to adopt explicit thresholds. For instance, 
the United States decision makers use variable thresholds, instead of 
rigidly fixed ones, as rough guides to help determine whether particular 
investments constitute reasonable value [32].
There are critics arguing that willingness-to-pay thresholds are 
unable to consider all the important social preferences and values, 
equity and distributive fairness [33]. Health technology assessment 
researchers agree that additional studies and efforts are needed to 
develop thresholds that clearly incorporate budget constraints and 
opportunity costs [33,34]. Therefore, WHO emphasizes that a fixed 
willingness-to-pay threshold should never be used as a stand-alone 
criterion for decision-making and its estimation is a challenge for 
health care systems [30].
Cost-effectiveness analysis of 3D compared to 2D 
brachytherapy 
Although 3D brachytherapy shows technical advantage and 
potentially superior clinical outcomes over conventional technique, 3D 
planning does carry added costs. Typically, 3D brachytherapy requires 
the acquisition of cross-sectional imaging for treatment planning with 
each fraction of brachytherapy [6,9]. This adds not only additional time 
for image acquisition and simulation, but it requires available imaging 
machines, that generally are used not only for brachytherapy, and 
increases length of treatment planning time and their associated costs. 
Whether the benefits afforded by 3D brachytherapy are cost-
effective is to be determined withing each health care system 
considering local context. For instance, Kim et al. investigated the 
cost-effectiveness of 3D brachytherapy compared to conventional 2D 
brachytherapy for the treatment of locally advanced cervical cancer 
from the perspective of Medicare US system [35]. They used a model-
based approach, where identical hypothetical cohorts treated with five 
fractions of intracavitary brachytherapy after external radiation therapy 
were followed during three years. For 3D brachytherapy, treatment 
was performed as either CT-based or MRI-based plan. The authors 
showed that the 3D CT-based strategy costs US$ 3003 more than 2D 
brachytherapy while gaining 0.16 QALYs, resulting in an ICER of US$ 
18,634 per QALY gained. The 3D MRI-based strategy costs US$ 4476 
more than 2D brachytherapy, resulting in an ICER of US$ 27,774 per 
QALY gained [35]. As the willingness-to-pay threshold adopted was 
US$ 50,000/QALY gained, the 3D strategies were considered cost-
effective technologies compared with 2D brachytherapy [35].
As discussed in the previous section, the results of the study 
published by Kim et al. are not transferrable to other health care 
contexts with distinct health policies, insurance and reimbursement 
systems, resources and priorities. 
Health care systems that progressively transitioned from 2D 
conventional to 3D brachytherapy, making their decision not-based on 
cost-effectiveness analyses, may consider such evaluations futile. Full 
economic evaluation studies become more relevant with the increasing 
cost scrutiny in health care, particularly in middle- and low-income 
countries as Brazil.
Conclusion
Technologies to treat cancer have received the most attention in the 
recent years, not only because of the increase of cases, but also because 
of the costs involved. Facing the promising, but still not definitive 
superiority of 3D compared to 2D brachytherapy, our research group 
is conducting a systematic review with meta-analyses to compare the 
effects of the two image planning technologies on clinical outcomes 
in patients with cervical cancer. A prospective cohort study will assess 
quality of life in patients treated with the two planning strategies. A 
systematic review of economic evaluation studies will be also carried 
Suzumura EA (2020) Do we need cost-effectiveness analysis of brachytherapy for cervical cancer in the 3D image-guided era?
 Volume 4: 4-4Cancer Rep Rev, 2020 doi: 10.15761/CRR.1000202
out to inform parameters to support the choice and construction of 
a model to perform a cost-effectiveness analysis of the treatment of 
cervical cancer with 3D brachytherapy versus 2D from the perspective 
of the Brazilian Unified Health System (Sistema Único de Saúde, 
SUS). These results may support the decision-making process about 
the incorporation of 3D brachytherapy in cancer programs, the 
development of clinical guidelines and national health policies.
Authorship and contributorship
Suzumura drafted the original manuscript. All authors made 
substantive intellectual contributions. All authors revised and approved 
the final manuscript.
Funding information
This study was partially supported by the Coordenação de 
Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – 
Finance Code 001. De Soarez PC is the recipient of grant from the 
Conselho Nacional de Desenvolvimento Cientifico e Tecnológico 
(CNPq, National Council of Technological and Scientific Development; 
Research Grant No. 302268/2019-7).
Competing interest
The authors have no conflict of interests to declare.
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Copyright: ©2020 Suzumura EA. This is an open-access article distributed 
under the terms of the Creative Commons Attribution License, which permits 
unrestricted use, distribution, and reproduction in any medium, provided the 
original author and source are credited.
https://www.ncbi.nlm.nih.gov/pubmed/29441104
https://www.ncbi.nlm.nih.gov/pubmed/20385450
https://www.ncbi.nlm.nih.gov/pubmed/25162885
https://www.ncbi.nlm.nih.gov/pubmed/25443528
	Title
	Correspondence
	Abstract
	Key words
	Introduction
	Treatment of cervical cancer 
	3D image-guided brachytherapy 
	Clinical effects of 3D compared to 2D brachytherapy 
	Understanding economic evaluation studies 
	Cost-effectiveness analysis of 3D compared to 2D brachytherapy 
	Conclusion
	Authorship and contributorship 
	Funding information 
	Competing interest 
	References